To the Editor,
We present the case of an 11-year-old female with a history of type 1
diabetes, hematochezia, and iron deficiency anemia who was admitted for
hypoxia following an endoscopy and colonoscopy. Room air saturations
were 80-85%, and she was started on oxygen by nasal cannula. A chest
radiograph (Figure 1a) demonstrated findings consistent with viral
airway disease, and on nasal swab she was positive for
rhino/enterovirus, but negative for COVID.
Further history from her grandmother, her primary caregiver, revealed
that the patient had lost weight over the past month, attributed to poor
appetite, with nausea, vomiting, and abdominal pain. The patient also
exhibited shortness of breath and increased work of breathing with
exertion over the past few months, but had no previous history of asthma
or lung disease. She had previously been anemic requiring transfusion
two months prior for a hemoglobin of 6 g/dL. On admission her hemoglobin
was 10.7g/dL.
On the third hospital day, the patient’s oxygen requirement increased,
prompting transfer to the pediatric intensive care unit (PICU). The
patient then developed intermittent hemoptysis, which could be
quantified at about a mouthful, warranting a chest computerized
tomography scan (CT), (Figure 1b) which was consistent with viral
infection or possible pulmonary hemorrhage. Flexible bronchoscopy was
performed, where saline lavage resulted in return of frank blood,
indicating the presence of pulmonary hemorrhage. Laboratory studies are
displayed in Table 1, most notable for elevated antineutrophil
cytoplasmic antibody (c-ANCA) of 1280. A lung biopsy was subsequently
performed which demonstrated signs of capillaritis with the presence of
many inflammatory cells, consistent with vasculitis, while
immunofluorescence was pauci immune.
Diagnosis of pediatric granulomatosis with polyangiitis (GPA) requires
three of the six following criteria: positive histopathology findings,
upper airway involvement, laryngo-trachea-bronchial stenosis, pulmonary
involvement, positivity by immunofluorescence or enzyme-linked
immunosorbent assay (ELISA), or renal involvement, with biopsy remaining
the gold standard.1 At this point, the patient now met
three of six criteria for GPA, (positive histopathology on biopsy,
pulmonary involvement, and positive ANCA) confirming that her hypoxemia
and hemorrhage were secondary to pulmonary involvement of GPA. Rituximab
and pulse doses of methylprednisolone were initiated, with subsequent
clinical improvement. Laboratory studies demonstrated a reduction of her
c-ANCA to 320 three weeks after initiation of therapy. She was
discharged home with a final diagnosis of c-ANCA positive GPA with
primary pulmonary involvement.
At follow up, pulmonary function testing (PFTs) showed forced vital
capacity (FVC) 67%, forced expiratory volume (FEV1) 71% and FEV1/FVC
ratio of 94%. At subsequent follow-up visits, she was noted to have
new-onset epistaxis with nasal septum perforation, meeting a fourth
criterion for GPA. She had received two doses of rituximab and was
started on Azathioprine, with a taper off prednisone over two months.
Eventually she no longer required supplemental oxygen, and her exercise
tolerance returned to normal. Her vital capacity improved to 85%
predicted and repeat chest CT scan showed significant improvement in the
interstitial disease pattern.
GPA is a type of ANCA-associated vasculitis (AAV) that affects the
capillaries, venules, and arterioles, most frequently exhibiting
c-ANCA/PR3-ANCA (proteinase 3) positivity.2 The
etiology of GPA has yet to be discovered; however, genetic and
environmental factors in combination with abnormalities in the innate
and adaptive immune system are thought to contribute to the disease
process.3 Clinically, GPA tends to involve the upper
respiratory tract, lower respiratory tract, and the renal system(s);
however, limited forms of the disease may occur and be confined to a
single organ.4 GPA in childhood tends to be more
severe compared to adult-onset with early, aggressive ear-nose-throat
(ENT) involvement (subglottic stenosis, nasal septal perforation). A
frequent presenting clinical manifestation of childhood GPA is pulmonary
involvement, demonstrated by shortness of breath, chronic cough, or
hemoptysis secondary to alveolar hemorrhage.5
Vasculitides, especially small artery vasculitis, are rare in the
pediatric population. The estimated prevalence of children with
ANCA-associated vasculitis is 3.41-4.28 per million children, with a
higher female predominance.3,4 Therefore, GPA was not
suspected for this young patient. It was only when all symptoms were put
together did a GPA diagnosis become clear.
In our patient, the late diagnosis was likely due to the individual
systemic presentations that were not obvious for vasculitis. Looking
back at the complete history, she presented with iron deficiency anemia,
shortness of breath, abdominal pain with subsequent hypoxia, and
hemoptysis. The dyspnea and abdominal pain were initially attributed to
anxiety caused by her complex social history, which included
incarcerated parents and transfer of care from the aunt to the
grandmother. In retrospect, the iron deficiency anemia, while treated
initially as an isolated event, was likely due to ongoing pulmonary
hemorrhage. Notably, pediatric patients usually present with suspicion
for GPA when in renal failure, however, our patient had consistently
normal kidney function. At what point in this constellation of symptoms
would a clinician have reasonably suspected GPA? The answer could easily
be never.
Another unique presentation of this patient was that she had a previous
diagnosis of Type 1 Diabetes (T1DM) and was later diagnosed with a
second autoimmune disorder, GPA. Comorbidities with multiple autoimmune
disorders are relatively common, however the research does not show GPA
as a known concurrent diagnosis. Was this patient an anomaly, or was she
more prone to GPA because of her existing T1DM? Given the little
information available, either is a possibility. It also brings into
question the management. Guidelines for GPA indicate that induction
therapy to achieve remission includes rituximab and prolonged use of
corticosteroids.3 In our patient, who has T1DM, it
questions whether this course of treatment was ideal. Overall, it shows
that management of dual autoimmune disorders affected by individual
treatment methods may need to be modified in future.
In summary, the incidence of childhood-onset GPA is exceedingly rare,
occurring in only 0.02 to 0.64 per 100,000 children per year, and is
nearly undocumented in the T1DM population.4 It is not
clearly understood whether this patient had a propensity toward
autoimmune diseases which increased her likelihood of developing GPA
while also having T1DM or if this combination is unrelated and
completely coincidental. Her history of present illness, including the
preceding months of various symptoms, led ultimately to a predominantly
pulmonary picture of dyspnea, hypoxia, and hemoptysis on initial
presentation without any renal involvement, unlike typical
GPA.6 For these reasons, one would need to have high
suspicion to include GPA in the differential diagnosis and workup of a
pediatric patient with hemoptysis. Recognizing and diagnosing childhood
GPA in a timely manner poses many challenges, as many pediatric cases do
not present with enough clinical features at one time to suspect the
diagnosis, leading to delayed or even missed diagnosis. One must have
high clinical suspicion so that appropriate treatment may be initiated.
References:
1. Calatroni M, Oliva E, Gianfreda D, et al. ANCA-associated vasculitis
in childhood: recent
advances. Ital J Pediatr. 2017;43(1):46.
https://doi:10.1186/s13052-017-0364-x
2. Cabral DA, Canter DL, Muscal E, et al. Comparing Presenting Clinical
Features in 48 Children with
Microscopic Polyangiitis to 183 Children Who Have Granulomatosis with
Polyangiitis
(Wegener’s): An ARChiVe Cohort Study. Arthritis Rheumatol.
2016;68(10):2514-2526.
https://doi.org/10.1002/art.39729
3. Jariwala M, Laxer RM. Childhood GPA, EGPA, and MPA. Clin Immunol
2020; 211:108325.
https://doi:10.1016/j.clim.2019.108325
4. Hirano D, Ishikawa T, Inaba A, et al. Epidemiology and clinical
features of childhood-onset antineutrophil cytoplasmic
antibody-associated vasculitis: a clinicopathological analysis. Pediatr
Nephrol. 2019;34(8):1425-1433.
https://doi:10.1007/s00467-019-04228-4
5. Filocamo G, Torreggiani S, Agostoni C, Esposito S. Lung involvement
in childhood onset
granulomatosis with polyangiitis. Pediatr Rheumatol Online J.
2017;15(1):28.
https://doi:10.1186/s12969-017-0150-8
6. Ludici M, Quartier P, Terrier B, Mouthon L, Guillevin L, Puéchal X.
Childhood-onset
granulomatosis with polyangiitis and microscopic polyangiitis:
systematic review and metaanalysis. Orphanet J Rare Dis.
2016;22;11(1):141.
https//: doi:10.1186/s13023-016-0523-y